Population pharmacokinetics of artesunate and its active metabolite dihydroartemisinin

Abstract

Artemisinin compounds are the most potent anti-malarial drugs available in the market. Today, malaria treatment is largely relies on the artemisinin-based combination therapies. Artesunate (AS) is the most widely used artemisinin derivative. In this thesis, we characterized the population pharmacokinetics of AS and its active metabolite dihydroartemisinin (DHA) following oral administration of AS in different populations. In Chapter II, we developed a population pharmacokinetic model of AS and DHA in healthy subjects. These subjects received either single-or multipledosing of oral AS, as a monotherapy regimen or in combination with pyronaridine, with or without food. In Chapter III, we developed a population pharmacokinetic model of AS and DHA in adult and pediatric patients with uncomplicated falciparum and vivax malaria who were administered oral pyronaridine/artesunate combination once daily for 3 days. We modeled the AS and DHA data simultaneously using a parent-metabolite model that assumed complete conversion of AS to DHA. Following oral administration, AS is rapidly absorbed with maximum concentrations reached at about 0.5 hours postdose. AS is rapidly converted to DHA. DHA then undergoes rapid metabolism, with an elimination half-life of about 0.8 hours in malarial patients. Inter-individual variability for almost all pharmacokinetic parameters and residual variability for both compounds were estimated by the models. Substantial variability was seen in the pharmacokinetic parameters between the subjects. In healthy subjects, intake of food with the dose was found to delay the absorption of AS significantly, but not the extent of absorption. Weight was also included in this model as a determinant of DHA clearance. When modeling the data from patients, we included weight as part of the model a priori using an established allometric function. No other covariates examined in the analysis were statistically significant. ACKNOWLEDGMENTS This work would never have been completed without the labor and support of many hands and minds, and thus my deepest gratitude goes to them: My mentor Dr. Larry Fleckenstein for his insightful discussion, inspiring work attitude and his ever open door. Drs. Erika Ernst, Lee Kirsch, Dawei Liu, and DJ Murry for being my committee members and for the comments and suggestions. Dr. Peter Veng-Pedersen for changing my perspective on pharmacokinetics and letting me sit in his class every year. My friends and colleagues Thitima Wattanavitjitkul for her support, motivation and the precious discussion, Dr. Himanshu Naik for his advice and encouragement, Denise Morris and Dr. Amal Al Omari for the powwows , Paul Imming and Mark Schmidt for the hard work in analyzing the samples, Grace Kim for checking the data, and Drs. Sherry Wei and George Lien for their kind assistance. My many friends in Iowa City who have extended their helping hands and kind words. The list is long, but you know who you are. Dr. Jitkang Lim for being a true friend of life. My family, both the Tan's and Larese-Casanov...

The effects of biogenic amines in Chinese Huangjiu on the behavior of mice and hangover headache‐related indices

“…Moreover, the ethanol in the serum of mice peaked at 0.5 h and gradually metabolized within 2.5 h after gavage (data not shown). These results are consistent with previous studies (Guang, 2016). Subsequently, the effects of the five types of BAs on mice behavior (moving distance, average speed, moving time, stagnation time, and number of stagnation periods) were evaluated at 0.5 and 2.5 h postgavage.…”